B cell maturation antigen, also known as BCMA; TR17_HUMAN, TNFRSF17 (Swissprot Acc. number Q02223), is a member of the tumor necrosis receptor superfamily that is preferentially expressed in mature B cells [Laabi et al. 1992; Madry et al. 1998]. BCMA is a non glycosylated type III transmembrane protein, which is involved in B cell maturation, growth and survival.
The human BCMA protein is a 184 amino acid polypeptide comprising an extracellular domain, located within the N-terminal region of the protein (amino acid residues 1-50), an intracellular domain (amino acid residues 94-184) and a transmembrane region (amino acid residues 51-93). The extracellular domain of BCMA comprises a six-cysteine-rich motif (characteristic of TNF-R molecules). This domain, although weakly similar to the consensus matrix of the cysteine-rich domain (CRD) mainly found on receptors for growth factors, still binds the TNF like protein. However, unlike some of the members of tumor necrosis necrosis receptor superfamily, BCMA intracellular region lacks a “death domain”, which is involved in TNF-mediated cell death signalling. The intracellular region, however, contains a 25 amino acid fragment (residues 119-143) that is essential for association with the TRAFs and activation of NF-κB. Since BCMA is a Type III transmembrane protein (i.e. the same sequence acts as both transmembrane and signal sequence), the BCMA gene does not contain a specific signal peptide sequence so that, under physiological conditions, the protein is mostly expressed within the Golgi membranes and not at the cell surface.
BCMA is a receptor for two ligands of the TNF superfamily: the B lymphocyte stimulator (mainly known as BlyS but described in the literature under various different names, including THANK, BAFF, B cell activator factor, TALL-1 and zTNF4); and APRIL (a proliferation-inducing ligand) [Hatzoglou et al. 2000 (PDF); Shu et al. 2000 (PDF); Gross et al. 2000 (PDF); Yu et al. 2000 (PDF); Marsters et al. 2000 (PAP)]. The coordinate binding of BLyS to BCMA and TACI (a distinct receptor: “transmembrane activator and CAML-interactor”) activates transcription factor NF-κB and increases expression of Bcl-2 that inhibits apoptosis. This combined action promotes B cell differentiation, proliferation and survival.
In this regard, BCMA is involved in the survival of long-lived bone marrow plasma cells [O'Connor et al. 2004 (PDF)], which negatively affects autoimmune diseases. Furthermore, on the basis of transgenic mouse experiments, it was suggested that BCMA might be involved in autoimmune diseases, such as lupus erythematosus (SLE) [Gross et al. 2000; Mackay et al. 1999; Khare et al. 2000]. BCMA is also involved in the development of humoral immunity (e.g., antibody production) and additional reports disclose a role for BCMA in various immune-related disorders (such as IBD or multiple sclerosis) as well as in cancers (for a complete review of the BCMA/BLyS system, please see Mackay et al. 2004). In this respect, various antagonists of BCMA have been proposed in the literature, for use in the treatment of immune diseases.
Such antagonists include antibodies against BCMA extracellular domain (e.g. WO02/66516) or soluble forms of BCMA, i.e., polypeptides comprising essentially the extracellular domain of BCMA and lacking an intracellular region. In this regard, several reports indicate that the isolated BCMA extracellular domain can be used therapeutically or in fusion proteins (WO00/40716, WO00/68378, WO01/60397, WO01/87977, WO03/35846, WO03/72713). Application number WO03/72713 provides methods and compositions for treating neurodegenerative immunological disorders in mammals by administering proteins comprising a soluble BCMA. The protein may include the full extracellular domain (residues 1-50), the CRD region (residues 8-41) or other generic smaller variants. BCMA-IgG fusion proteins have also been disclosed in the literature, having therapeutic properties against autoimmune diseases or cancers [Rennert et al. 2000; Yu et al. 2000; Pelletier et al. 2003]. Also, the ligand-binding domain of BCMA has been studied by mutagenesis, giving rise to variants thereof with different affinity/specificity, that have used fusion proteins [Patel et al. 2004]. Deletion variants of BCMA intracellular region are also disclosed in Hatzoglou et al. 2000.
BCMA thus represents a recognized target for the treatment of various pathological conditions in human subjects, and the development of effective antagonist or alternative BCMA polypeptides would be of high value for the pharmaceutical industry.